CN104341352A - Diaryl hydantoin compound as androgen receptor antagonist and applications of diaryl hydantoin compound - Google Patents

Diaryl hydantoin compound as androgen receptor antagonist and applications of diaryl hydantoin compound Download PDF

Info

Publication number
CN104341352A
CN104341352A CN201310348139.0A CN201310348139A CN104341352A CN 104341352 A CN104341352 A CN 104341352A CN 201310348139 A CN201310348139 A CN 201310348139A CN 104341352 A CN104341352 A CN 104341352A
Authority
CN
China
Prior art keywords
deuterium
hydrogen
acid
halogen
alkyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
CN201310348139.0A
Other languages
Chinese (zh)
Inventor
张维威
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
NANJING HENGJIE BIOTECHNOLOGY Co Ltd
Original Assignee
NANJING HENGJIE BIOTECHNOLOGY Co Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by NANJING HENGJIE BIOTECHNOLOGY Co Ltd filed Critical NANJING HENGJIE BIOTECHNOLOGY Co Ltd
Priority to CN201310348139.0A priority Critical patent/CN104341352A/en
Publication of CN104341352A publication Critical patent/CN104341352A/en
Pending legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D233/86—Oxygen and sulfur atoms, e.g. thiohydantoin

Abstract

The invention relates to diaryl hydantoin compounds of general formula (I), and derivatives, pharmaceutically acceptable salts and solvates of the diaryl hydantoin compounds, as well as applications thereof in treatment of hormone refractory prostate cancer and breast cancer. The structural formula is as shown in the description, wherein R1-R5, G and X are as defined in the description.

Description

As Diarylhydantoin compounds and the application thereof of androgen receptor antagonists
Technical field
The present invention relates to new Diarylhydantoin compounds, their derivative, pharmacologically acceptable salts, hydrate or solvate, and their application in the treatment prostate cancer of hormone refractory, mammary cancer.
Background technology
Prostate cancer is the common cancer of elderly men, and in western countries, prostate cancer mortality ratio is only second to lung cancer, ranked second position.In China, the past is fewer for the understanding of prostate cancer, prostate cancer China so that whole Asia incidence all lower, along with the propelling of examination and generation, this data consistent is riseing.In the male sex of prostate cancer before 45 one full year of life, incidence is extremely low, in elderly men, sickness rate is high, along with the raising of social life level and the improvement of medical condition, the mean lifetime significant prolongation of population, the growth of population and the aging population of Chinese society cannot be avoided, and this makes the sickness rate of Chinese prostate cancer by continuation in the situation that rapidly rises.
When there is prostate cancer, when cancer is limited in local time, this disease can by operation or radiotherapy.But this type of cancer of 30% is along with far-end metabolic disease and other illnesss recurrence in diagnosis with grave illness.Grave illness is performed the operation by castration and/or administration antiandrogen therapy, is referred to as androgen deprivation therapy.Castration operation decreases circulation androgen levels, and antiandrogen is combined by competition male sex hormone and blocks androgen receptor (AR) function, therefore reduces AR active.Although start effectively, these treatments have failed soon, and cancer becomes Hormone refractory.
At present, the process LAN of AR has enough made prostate cancer develop into hormone refractory from hormone-sensitive, AR and be required with the growth of part to the prostate cancer of hormone refractory that it combines; Simultaneously anti-male material is converted into agonist from antagonist by the process LAN of AR in the prostate cancer of hormone refractory, this also explains why castration and antiandrogen can not stop the development of prostate cancer and disclose the special property of the prostate cancer of hormone refractory.
Bicalutamide is conventional antiandrogen.Although it is inhibited to the AR in hormone-sensitive prostate cancer, when cancer becomes hormonal resistance, it can not suppress AR.Because it can not stop prostate cancer to be developed to the hormonal resistance stage from hormone-sensitive stage, effectively can not treat the prostate cancer of hormone refractory, these two shortcomings are treatment bottlenecks of current antiandrogen.So, need that there is more effective antagonistic activity, and the prostate cancer of fatal hormone refractory treated by the AR inhibitor of agonist activity minimum in AR process LAN situation.
The confirmation with the compound of the active and minimum agonist activity of efficient androgen antagonist should overcome the prostate cancer of hormone refractory and avoid or slow down the development of hormone-sensitive prostate cancer.Therefore, needing the selective modulator confirming androgen receptor in the art, such as, is the conditioning agent of nonsteroidal, nontoxicity and tissue selectivity.
At second half of the mankind--woman, mammary cancer is their a large chronic disease of long-standing problem equally.It is generally acknowledged that estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor-2 (Her-2) are modal 3 large driving factors.In recent years, it is found that male sex hormone (AR) is also the driving factors of mammary cancer, block the growth that AR can stop some mammary cancer, therefore Anti-androgenic compounds also has very large Development volue in the treatment of mammary cancer.
Summary of the invention
The invention provides a series of compounds AR to strong antagonistic activity and minimum agonist activity.The prostate cancer of these compound inhibitory hormone refractories, the development of mammary cancer.
According to an aspect of the present invention, it provides with the compound of following formula I or its pharmacologically acceptable salts, hydrate or solvate:
Wherein:
R 1, R 2and R 3be C independently 1-C 5alkyl, the one or more hydrogen atoms in this alkyl are optionally replaced by deuterium; Or
R 1and R 2form 3-6 ring together with the carbon atom that they connect, the one or more hydrogen atoms on this ring are optionally replaced by deuterium, and R 3for C 1-C 5alkyl, the one or more hydrogen atoms in this alkyl are optionally replaced by deuterium;
R 4be selected from hydrogen, deuterium, halogen and cyano group;
R 5be selected from hydrogen, deuterium, halogen and trifluoromethyl;
G is selected from oxygen or sulphur;
X is selected from hydrogen, deuterium and halogen;
Condition is R 1-R 5and containing at least one D atom in X.
In an embodiment of formula I, R 1, R 2and R 3independently selected from CH 3, CH 2d, CHD 2and CD 3.
In an embodiment of formula I, it has the structure with Formula Il:
Wherein:
R 1, R 2and R 6independently selected from CH 2, CHD and CD 2;
R 3for C 1-C 5alkyl, the one or more hydrogen atoms in this alkyl are optionally replaced by deuterium;
R4 is selected from hydrogen, deuterium, halogen and cyano group;
R 5be selected from hydrogen, deuterium, halogen and trifluoromethyl;
G is selected from oxygen or sulphur;
X is selected from hydrogen, deuterium and halogen;
Condition is R 1-R 6and containing at least one D atom in X.
In an embodiment of formula I, it has the structure of following formula III:
Wherein:
R 1, R 2, R 7and R 8independently be selected from CH 2, CHD and CD 2;
R 3for C 1-C 5alkyl, the one or more hydrogen atoms in this alkyl are optionally replaced by deuterium; Be preferably CH 3, CH 2d, CHD 2or CD 3.
R 4be selected from hydrogen, deuterium, halogen, cyano group;
R 5be selected from hydrogen, deuterium, halogen, trifluoromethyl;
G is selected from oxygen or sulphur;
X is selected from hydrogen, deuterium, halogen;
In addition, condition is R 1-R 8and containing at least one D atom in X.
In an embodiment of formula I, it is
Or
According to another aspect of the present invention, it comprises a kind of pharmaceutical composition being used for the treatment of hyperproliferative disorders, and it comprises according to above-claimed cpd of the present invention or its pharmacologically acceptable salt, hydrate or solvate, and pharmaceutically acceptable carrier or vehicle.
According to another aspect of the present invention, it relates to the application in the medicine for the preparation of overmedication proliferative disorders according to above-claimed cpd of the present invention or its pharmacologically acceptable salt, hydrate or solvate.This hyperproliferative disorders is prostate cancer or mammary cancer.
In an embodiment of this application, described medicine is for disturbing transcribing of prostate specific antigen mRNA.
In an embodiment of this application, described medicine is the core transposition for preventing androgen receptor protein matter.
The present invention also comprises the method being used for the treatment of hyperproliferative disorders, comprises the patient's administration to this treatment of needs of above-claimed cpd according to the present invention or pharmaceutical composition.Hyperproliferative disorders can be the prostate cancer of hormone refractory and the mammary cancer of male sex hormone process LAN.
Accompanying drawing explanation
Fig. 1 is that grace mixes Shandong amine, AYJ60113 to the inhibiting comparison diagram of tumor bearing nude mice tumor growth.
Embodiment
In one embodiment, compound according to the present invention has following formula:
Wherein
R 3be selected from CH 3, CH 2d, CHD 2and CD 3;
R 4be selected from hydrogen, deuterium, halogen and cyano group;
R 5be selected from hydrogen, deuterium, halogen and trifluoromethyl;
G is selected from oxygen or sulphur;
X is selected from hydrogen, deuterium and halogen;
Condition is: R 3-R 5and containing at least one D atom in X.
Concrete compound such as can have following formula:
In the disclosure, term " halogen " should be understood and is expressed as fluorine, chlorine, bromine or iodine atom, preferred fluorine, chlorine, bromine or iodine atom.
In the disclosure, term " C 1-C 5alkyl " be interpreted as preferably representing that there is the straight or branched of 1,2,3,4 or 5 carbon atom, saturated monovalent hydrocarbon; such as methyl, ethyl, propyl group, butyl, amyl group, sec.-propyl, isobutyl-, sec-butyl, the tertiary butyl, isopentyl, 2-methyl butyl, 1-methyl butyl, 1-ethyl propyl, 1; 2-dimethyl propyl, neo-pentyl, 1; 1-dimethyl propyl, 4-methyl amyl, 3-methyl amyl, 2-methyl amyl or 1-methyl amyl, or their isomer.Especially, described group has 1,2,3 or 4 carbon atom (" C 1-C 4-alkyl "), such as methyl, ethyl, propyl group, butyl, sec.-propyl, isobutyl-, sec-butyl, the tertiary butyl, more particularly, described group has 1,2 or 3 carbon atom (" C 1-C 3-alkyl "), such as methyl, ethyl, n-propyl or sec.-propyl.
In the present invention, above-mentioned C 1-C 5one or more hydrogen atoms in alkyl can be replaced by deuterium, such as, be CH 3, CH 2d, CHD 2, CD 3.
Compound of the present invention can the form of hydrate or solvate exist, and wherein compound of the present invention comprises the polar solvent of the textural element as described compound lattice, particularly such as water, methyl alcohol or ethanol.The amount of polar solvent particularly water can stoichiometric ratio or non-stoichiometric exist.When stoichiometric solvates is as hydrate, may be half (hemi-) solvate or hydrate, (half (semi-)) solvate or hydrate, a solvate or hydrate, sesquialter solvate or hydrate, two solvates or hydrate, three solvates or hydrate, four solvates or hydrate, five solvates or hydrate etc. respectively.The present invention includes all this kind of hydrates or solvate.
In addition, compound of the present invention can exist in a free form, such as, with free alkali or free acid or zwitterionic form, or can exist in a salt form.Described salt can be any salt, and it can be the acceptable organic or inorganic additive salt of any pharmacy conventional in organic or inorganic additive salt, particularly pharmacy.
Term " pharmacologically acceptable salts " refer to the relative nontoxic of compound of the present invention, mineral acid or organic acid addition salt.Such as, see S.M.Berge, et al. " Pharmaceutical Salts, " J.Pharm.Sci.1977,66,1-19.
The suitable pharmacologically acceptable salts of the compounds of this invention can be the acid salt with the compounds of this invention of enough alkalescence such as comprising nitrogen-atoms in chain or ring, the acid salt such as formed with following mineral acid: such as hydrochloric acid, Hydrogen bromide, hydroiodic acid HI, sulfuric acid, pyrosulfuric acid (bisulfuric acid), phosphoric acid or nitric acid, or the acid salt formed with following organic acid: such as formic acid, acetic acid, etheric acid, pyruvic acid, trifluoroacetic acid, propionic acid, butyric acid, caproic acid, enanthic acid, undecanoic acid, lauric acid, phenylformic acid, Whitfield's ointment, 2-(4-hydroxy benzoyl) phenylformic acid, dextrocamphoric acid, styracin, pentamethylene propionic acid, didextrose acid (digluconic acid), 3-hydroxy-2-naphthoic acid, nicotinic acid, flutter acid, pectinic acid, persulfuric acid, 3-phenylpropionic acid, picric acid, trimethylacetic acid, 2-ethylenehydrinsulfonic acid, methylene-succinic acid, thionamic acid, trifluoromethanesulfonic acid, dodecyl sulphate, ethyl sulfonic acid, Phenylsulfonic acid, tosic acid, methylsulfonic acid, 2-naphthene sulfonic acid, naphthalene disulfonic acid, camphorsulfonic acid, citric acid, tartrate, stearic acid, lactic acid, oxalic acid, propanedioic acid, succsinic acid, oxysuccinic acid, adipic acid, alginic acid, toxilic acid, fumaric acid, D-glyconic acid, amygdalic acid, xitix, glucoheptose, Phosphoric acid glycerol esters, aspartic acid, sulphosalicylic acid, hemisulfic acid (hemisulfuric acid) or thiocyanic acid.
In addition, the pharmacologically acceptable salts having the another kind of enough acid the compounds of this invention suitable is that an alkali metal salt is as sodium salt or sylvite, alkaline earth salt is as calcium salt or magnesium salts, ammonium salt, or with the physiology salt that acceptable cationic organic bases is formed is provided, the salt such as formed with following material: N-methyl-glucamine, dimethyl-glycosamine, ethyl-glycosamine, Methionin, dicyclohexylamine, 1, 6-hexanediamine, thanomin, glycosamine, sarkosine, serinol, three-hydroxy-methyl-aminomethane, amino-propanediol, sovak-alkali, 1-amino-2, 3, 4-trihydroxybutane.In addition, Basic nitrogen-containing groups can be quaternized with following reagent: low alkyl group halogen, such as methyl, ethyl, propyl group and Butyryl Chloride compound, bromide and iodide; Dialkyl sulfate, such as methyl-sulfate, ethyl sulfate, dibutyl sulfate and diamyl sulfates; Long chain halide is decyl, lauryl, myristyl and stearyl chlorides, bromide and iodide such as; Aralkyl halide is as benzyl and phenylethyl bromide etc.
Those skilled in the art can recognize further, and the acid salt of compound required for protection can make described compound prepare with suitable mineral acid or organic acid reaction by any one in multiple currently known methods.Or an alkali metal salt of acidic cpd of the present invention and alkaline earth salt make compound of the present invention and suitable alkali reaction prepare by various known method.
The present invention includes all possible salt of the compounds of this invention, it is any mixture of any ratio of single salt or described salt.
In addition, the present invention includes all possible crystallized form or the polymorphic form of the compounds of this invention, it can be the mixture of single polycrystalline type thing or any ratio more than a kind of polymorphic form.
In one embodiment, the present invention relates to a kind of pharmaceutical composition being used for the treatment of hyperproliferative disorders, it comprises according to compound or pharmaceutically acceptable salt thereof of the present invention, hydrate or solvate, and pharmaceutically acceptable carrier or vehicle.
In another embodiment, the present invention includes the method being used for the treatment of hyperproliferative disorders and comprise the patient administration of the pharmaceutical composition of claim 1 to this treatment of needs, overmedication proliferative disorders thus.
Said composition can such as have the form being selected from solution, dispersion, suspension, powder, capsule, tablet, pill, time-release capsules, time release tablet and time release pill.This compound is by intravenous administration, by being injected into the medicine organized in administration, Intraperitoneal medication, oral administration or nose and give to treat significant quantity.
Be used for the treatment of prostate cancer, the method for mammary cancer comprises the patient administration of pharmaceutical composition to this treatment of needs, treat prostate cancer, mammary cancer thus.This pharmaceutical composition can disturb transcribing of prostate specific antigen mRNA.This pharmaceutical composition can prevent the core transposition of androgen receptor protein matter.This pharmaceutical composition can make androgen receptor protein matter unstable.Said composition Orally-administrable.Said composition can have the form being selected from capsule, tablet and pill.
Based on the known standard laboratory techniques being used for evaluating the compound that can be used for overmedication proliferative disorders, by standard toxotest and by measuring the Standard pharmacological of the treatment of disease condition mentioned above in Mammals for determining, and by by these results be used for the result of the known drug for the treatment of these disease conditions and compare, easily can determine the effective dose of the compound of the present invention for the treatment of the indication that often kind is expected.In the treatment of one of these disease conditions the activeconstituents of administration amount can great changes will take place according to following considering: the age of specific compound used and dose unit, administering mode, the course for the treatment of, subject patient and sex and the nature and extent of disease condition for the treatment of.
The total amount of activeconstituents to be administered is generally about 0.001mg/kg-and is about 200mg/kg body weight/day, and preferably about 0.01mg/kg-is about 20mg/kg body weight/day.Clinically can dosage regimen be every day the dosed administration of to three time to every surrounding dosed administration once.In addition, " withdrawal time " (wherein not giving Patient drug within certain for some time) may be favourable for the whole machine balancing between pharmacological efficacy and tolerance.Unitary dose can comprise about 0.5mg-and be about 1500mg activeconstituents, and once a day or administration in multiple times, or can be less than administration once a day.By comprise intravenously, intramuscular, subcutaneous and parenteral injection injection and use the ADD of infusion techniques administration to be preferably 0.01-200mg/kg TBW.
Certainly, the concrete initial dose of every patient and maintenance dose scheme can change according to following factor: the discharge rate, drug regimen etc. of the character of the determined disease condition of clinical diagnosis doctor and severity, the activity of particular compound used, the age of described patient and holistic health, administration time, route of administration, medicine.The therapeutic modality of the expectation of compound of the present invention, its pharmacologically acceptable salts, hydrate or solvate and dose quantity can utilize conventional treatment test to determine by those skilled in the art.
The method of synthesis following formula biaryl compound
The method comprises the following steps: by Compound I 1or I 2in the first polar solvent (as DMF etc.), mix to form mixture with Compound II per,
Wherein, R 3, R 4, R 5and X
Then this mixture is heated, then second polar solvent (as methyl alcohol etc.) identical or different with the first polar solvent and aqueous acids (example hydrochloric acid etc.) is added, reflux this mixture, cools this mixture and mix with water, finally by being separated in mixture according to biaryl compound of the present invention.
Such as, for synthesis AYJ60113, the method comprises: by N-methyl-d 3the fluoro-4-(1 of-2-, 1-dimethyl-cyanomethyl)-aminobenzamide and the different thiocyanato of 4--2-Trifluoromethylbenzonitrile in high bp polar solvent (as DMF) Hybrid Heating to form the first mixture, methyl alcohol and hydrochloric acid is added in the first mixture, back flow reaction, form the second mixture, second mixture is cooled to room temperature, is added to the water, and is extracted with ethyl acetate to obtain product A YJ60113.
Below with reference to embodiment, the present invention is made a more detailed description.But it will be understood by those skilled in the art that scope of the present invention is not limited in these embodiments, they be only for illustration of object.
Embodiment
Embodiment 1:N-methyl-d 3the synthesis of the fluoro-4-nitrobenzamide of-2-
At sulfur oxychloride (0.15g, 1.3mmol) is slowly added in-5 DEG C cooling the fluoro-4-nitrobenzoic acid (0.20g, 1.10mmol) of 2-at DMF(5ml) in solution in.Mixture is stirred 1 hour again at-5 DEG C.Excessive deuterated methylamine (being total to heat from its hydrochloride and sodium hydroxide free) is added reaction medium.This second mixture is stirred 1 hour again.Ethyl acetate (50ml) is added this mixture, washs with hydrochloric acid (2 × 50ml).Organic layer MgSO 4drying, concentrates and obtains N-methyl-d 3the fluoro-4-nitrobenzamide of-2-(0.16g, 0.75%).
1h NMR δ 6.31(dd, 1H, J=13.5 and 2.1), 6.40(dd, 1H, J=8.6 and 2.1) and, 7.64(dd, 1H, J=8.6 and 8.6).
MS（ESI）m/z：201.06。
Embodiment 2:N-methyl-d 3the synthesis of the fluoro-4-aminobenzamide of-2-
By N-methyl-d 3the backflow 1 hour in the mixed solution of ethyl acetate (5ml) and acetic acid (5ml) of the fluoro-4-nitrobenzamide (0.18g, 0.91mmol) of-2-and iron (0.31g, 5.60mmol).Filters solid particles.Filtrate water washs, extraction into ethyl acetate.Organic layer is dry, and column chromatography obtains pale solid (0.14g, 92%).
1h NMR δ 5.50(br s, 2H), 6.37(dd, 1H, J=14.7 and 2.1), 6.50(dd, 1H, J=8.6 and 2.1) and, 7.06(br s, 1H), 7.68(dd, 1H, J=8.8 and 8.8).
MS（ESI）m/z：171.09。
Fluoro-4-(1, the 1-dimethyl-cyanomethyl of embodiment 3:N-methyl-d3-2-) synthesis of-aminobenzamide
By N-methyl-d 3the mixture of the fluoro-4-aminobenzamide (96mg, 0.57mmol) of-2-, acetone cyanohydrin (0.3ml, 3.14mmol) and magnesium sulfate (50mg) is heated to 80 DEG C, stirs 12 hours.In reaction solution, add ethyl acetate (25ml), wash with water.By organic layer MgSO 4drying is also concentrated, and column chromatography purification obtains N-methyl-d 3fluoro-4-(1, the 1-dimethyl-cyanomethyl of-2-)-aminobenzamide (101mg, 75%) is white solid.
1h NMR δ 1.74(s, 6H), 6.58(dd, 1H, J=14.6 and 2.3), 6.63(dd, 1H, J=8.7 and 2.3) and, 6.66(br s, 1H), 7.94(dd, 1H, J=8.7 and 8.7).
MS（ESI）m/z：238.13。
The synthesis of the different thiocyanato of embodiment 4:4--2-Trifluoromethylbenzonitrile
4-amino-2-Trifluoromethylbenzonitrile (2.23g, 12mmol) is added in batches thiophosgene (1ml, 13mmol) stirring reaction 1.5 hours in toluene (25ml) at room temperature 15 minutes.Reaction product is spin-dried for solvent, with column chromatography, obtains light tan solid (2.50g, 10.9mmol, 91.8%).
1h NMR δ 7.49(dd, 1H, J=8.3 and 2.1), 7.59(d, 1H, J=2.1) and, 7.84(d, 1H, J=8.3).
MS（ESI）m/z：228.00。
The synthesis of embodiment 5:AYJ60113
By N-methyl-d 3fluoro-4-(1, the 1-dimethyl-cyanomethyl of-2-)-aminobenzamide (30mg, 0.13mmol) and the different thiocyanato of 4--2-Trifluoromethylbenzonitrile (58mg, 0.26mmol) be at DMF(1ml) in mixture react 12 hours at 100 DEG C.Methyl alcohol (20ml) and the 1N HCl aqueous solution (5ml) is added in mixed solution.Again heat, back flow reaction 1.5 hours.After being cooled to room temperature, reaction mixing is poured in cold water (50ml), extract by ethyl acetate (50ml).Organic layer MgSO 4drying, concentrated, with column chromatography purification, obtain colourless crystallization (15mg, 25%).
1h NMR δ 1.61(s, 6H), 6.71(m, 1H), 7.15(dd, 1H, J=11.7 and 2.0) and, 7.24(dd, 1H, J=8.4 and 2.0), 7.83(dd, 1H, J=8.2 and 2.1), 7.95(d, 1H, J=2.1), 7.99(d, 1H, J=8.2), 8.28(dd, 1H, J=8.4 and 8.4).
MS（ESI）m/z：467.11。
The synthesis of embodiment 6:AYJ60112
The synthesis of AYJ60112 and relevant intermediate is consistent with the synthetic method in embodiment 1-5, and difference is finally to synthesize N-methyl-d by the methylamine hydrochloride infiltration reaction starting raw material that employing one is deuterated 1fluoro-4-(1, the 1-dimethyl-cyanomethyl of-2-)-aminobenzamide and the different thiocyanato of 4--2-Trifluoromethylbenzonitrile react, as follows:
By N-methyl-d 1fluoro-4-(1, the 1-dimethyl-cyanomethyl of-2-)-aminobenzamide (30mg, 0.13mmol) and the different thiocyanato of 4--2-Trifluoromethylbenzonitrile (58mg, 0.26mmol) be at DMF(1ml) in mixture react 12 hours at 100 DEG C.Methyl alcohol (20ml) and the 1N HCl aqueous solution (5ml) is added in mixed solution.Again heat, back flow reaction 1.5 hours.After being cooled to room temperature, reaction mixing is poured in cold water (50ml), extract by ethyl acetate (50ml).Organic layer MgSO 4drying, concentrated, with column chromatography purification, obtain colourless crystallization (15mg, 25%).
1h NMR δ 1.61(s, 6H), 3.12 (d, 2H), 6.71(m, 1H), 7.15(dd, 1H, J=11.7 and 2.0), 7.24(dd, 1H, J=8.4 and 2.0), 7.83(dd, 1H, J=8.2 and 2.1), 7.95(d, 1H, J=2.1), 7.99(d, 1H, J=8.2), 8.28(dd, 1H, J=8.4 and 8.4).
MS（ESI）m/z：465.10。
The synthesis of embodiment 7:AYJ60114
The synthesis of AYJ60114 and relevant intermediate is consistent with the synthetic method in embodiment 1-5, and difference is finally to synthesize N-methyl-d by the methylamine hydrochloride infiltration reaction starting raw material that employing two is deuterated 1fluoro-4-(1, the 1-dimethyl-cyanomethyl of-2-)-aminobenzamide and the different thiocyanato of 4--2-Trifluoromethylbenzonitrile react, as follows:
By N-methyl-d 1fluoro-4-(1, the 1-dimethyl-cyanomethyl of-2-)-aminobenzamide (30mg, 0.13mmol) and the different thiocyanato of 4--2-Trifluoromethylbenzonitrile (58mg, 0.26mmol) be at DMF(1ml) in mixture react 12 hours at 100 DEG C.Methyl alcohol (20ml) and the 1N HCl aqueous solution (5ml) is added in mixed solution.Again heat, back flow reaction 1.5 hours.After being cooled to room temperature, reaction mixing is poured in cold water (50ml), extract by ethyl acetate (50ml).Organic layer MgSO 4drying, concentrated, with column chromatography purification, obtain colourless crystallization (15mg, 25%).
1h NMR δ 1.61(s, 6H), 3.12 (d, 1H), 6.71(m, 1H), 7.15(dd, 1H, J=11.7 and 2.0), 7.24(dd, 1H, J=8.4 and 2.0), 7.83(dd, 1H, J=8.2 and 2.1), 7.95(d, 1H, J=2.1), 7.99(d, 1H, J=8.2), 8.28(dd, 1H, J=8.4 and 8.4).
MS（ESI）m/z：466.11。
Embodiment 8
Nude mice (nu/nu, male.) subcutaneous vaccination Human Prostate Cancer Cells PC-3(inoculum size=5 × 10 of about 18g 6/ only), treat that knurl volume reaches 100mm 3time above, grouping, grace is mixed Shandong amine
(enzalutamide, Xtandi) and AYJ60113 two compounds are all according to the dosage gastric infusion of 12mg/kg, and within every 4 days, measure a knurl volume, result is as follows:
Mix Shandong amine and AYJ60113 group of compound grace to compare with blank group in the measurement result of administration after 8 days and has significant difference (P<0.05vs control group), and the tumor suppression of administration AYJ60113 after 16 days is significantly better than grace and mixes Shandong amine.At the end of administration (24 days) grace mix Shandong amine and AYJ60113 to the inhibiting rate of PC-3 tumor growth [(before and after the administration of pathological model treated animal knurl volume velocity of variation-test group animals administer before and after the velocity of variation of knurl volume) velocity of variation of animal knurl volume before and after/pathological model group administration] be respectively 56.1%(and compare with pathological model, p<0.01) and 73.6%(compare with pathological model, p<0.01), and AYJ60113 is significantly better than grace to the restraining effect of prostate carcinoma cell growth mixes Shandong amine (p<0.01), active high 31.2%.Result as shown in Figure 1.
In addition, while the drug effect of AYJ60113 mixes Shandong amine apparently higher than grace, the body weight change giving the nude mice of AYJ60113 and grace Shandong amine of mixing compares, and without significant difference, the toxicity that AYJ60113 is described not to be mixed Shandong amine higher than compound grace.
Embodiment 9
Nude mice (nu/nu, Female) in-situ inoculating MCF-7 Breast Cancer Cell (inoculum size=5 × 10 of about 18g 6/ only), treat that knurl volume reaches 100mm 3time above, grouping, grace mixes Shandong amine (enzalutamide, Xtandi) and AYJ60113 two compounds all according to the dosage gastric infusion of 15mg/kg.Measure weekly twice knurl volume and body weight, result display AYJ60113 more than 60% to the inhibiting rate of tumor growth, and is significantly better than grace and mixes the body weight change no significant difference of Shandong amine (p<0.05), two treated animals.

Claims (11)

1. the compound of formula I or its pharmacologically acceptable salts, hydrate or solvate:
Wherein:
R 1, R 2and R 3be C independently 1-C 5alkyl, the one or more hydrogen atoms in this alkyl are optionally replaced by deuterium; Or
R 1and R 2form 3-6 ring together with the carbon atom that they connect, the one or more hydrogen atoms on this ring are optionally replaced by deuterium, and R 3for C 1-C 5alkyl, the one or more hydrogen atoms in this alkyl are optionally replaced by deuterium;
R 4be selected from hydrogen, deuterium, halogen and cyano group;
R 5be selected from hydrogen, deuterium, halogen and trifluoromethyl;
G is selected from oxygen or sulphur;
X is selected from hydrogen, deuterium and halogen;
Condition is R 1-R 5and containing at least one D atom in X.
2. compound according to claim 1, wherein R 1, R 2and R 3independently selected from CH 3, CH 2d, CHD 2and CD 3.
3. compound according to claim 1, it has the structure with Formula Il:
Wherein:
R 1, R 2and R 6independently selected from CH 2, CHD and CD 2;
R 3for C 1-C 5alkyl, the one or more hydrogen atoms in this alkyl are optionally replaced by deuterium;
R4 is selected from hydrogen, deuterium, halogen and cyano group;
R 5be selected from hydrogen, deuterium, halogen and trifluoromethyl;
G is selected from oxygen or sulphur;
X is selected from hydrogen, deuterium and halogen;
Condition is R 1-R 6and containing at least one D atom in X.
4. compound according to claim 1, it has the structure of following formula III:
Wherein:
R 1, R 2, R 7and R 8independently be selected from CH 2, CHD and CD 2;
R 3for C 1-C 5alkyl, the one or more hydrogen atoms in this alkyl are optionally replaced by deuterium;
R 4be selected from hydrogen, deuterium, halogen, cyano group;
R 5be selected from hydrogen, deuterium, halogen, trifluoromethyl;
G is selected from oxygen or sulphur;
X is selected from hydrogen, deuterium, halogen;
In addition, condition is R 1-R 8and containing at least one D atom in X.
5. according to the compound of claim 3 or 4, wherein R 3for CH 3, CH 2d, CHD 2or CD 3.
6. compound according to claim 1, it is
Or
7. be used for the treatment of the pharmaceutical composition of hyperproliferative disorders, it comprises compound or pharmaceutically acceptable salt thereof as claimed in one of claims 1-6, hydrate or solvate, and pharmaceutically acceptable carrier or vehicle.
8. compound or pharmaceutically acceptable salt thereof as claimed in one of claims 1-6, hydrate or the solvate application in the medicine for the preparation of overmedication proliferative disorders.
9. application according to claim 8, wherein said hyperproliferative disorders is prostate cancer or mammary cancer.
10. the application of according to Claim 8 or 9, wherein said medicine is for disturbing transcribing of prostate specific antigen mRNA.
11. the application of according to Claim 8 or 9, wherein said medicine is the core transposition for preventing androgen receptor protein matter.
CN201310348139.0A 2013-08-09 2013-08-09 Diaryl hydantoin compound as androgen receptor antagonist and applications of diaryl hydantoin compound Pending CN104341352A (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN201310348139.0A CN104341352A (en) 2013-08-09 2013-08-09 Diaryl hydantoin compound as androgen receptor antagonist and applications of diaryl hydantoin compound

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN201310348139.0A CN104341352A (en) 2013-08-09 2013-08-09 Diaryl hydantoin compound as androgen receptor antagonist and applications of diaryl hydantoin compound

Publications (1)

Publication Number Publication Date
CN104341352A true CN104341352A (en) 2015-02-11

Family

ID=52497883

Family Applications (1)

Application Number Title Priority Date Filing Date
CN201310348139.0A Pending CN104341352A (en) 2013-08-09 2013-08-09 Diaryl hydantoin compound as androgen receptor antagonist and applications of diaryl hydantoin compound

Country Status (1)

Country Link
CN (1) CN104341352A (en)

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN106432090A (en) * 2015-10-30 2017-02-22 成都海创药业有限公司 Crystal form of deuteration imidazolone compound and preparation method and use of crystal form
JP2019532075A (en) * 2016-10-17 2019-11-07 ヒノバ ファーマシューティカルズ インコーポレイテッド Process for preparing deuterated imidazolidinedione compounds
CN111032644A (en) * 2017-08-07 2020-04-17 正大天晴药业集团股份有限公司 Diarylthiohydantoin compounds useful as androgen receptor antagonists
WO2020156448A1 (en) * 2019-02-01 2020-08-06 正大天晴药业集团股份有限公司 Crystal of diarylthiohydantoin compound
JP2021519322A (en) * 2018-03-29 2021-08-10 ヒノバ ファーマシューティカルズ インコーポレイテッド Deuterated imidazolidinedione compounds and their uses
CN115181043A (en) * 2022-07-27 2022-10-14 爱斯特（成都）生物制药股份有限公司 Method for preparing 4-isothiocyanato-2- (trifluoromethyl) benzonitrile by continuous flow
CN117164520A (en) * 2022-01-28 2023-12-05 南京思聚生物医药有限公司 Androgen receptor antagonist with local action and application thereof
RU2810214C2 (en) * 2019-02-01 2023-12-25 Чиа Тай Тянцин Фармасьютикал Груп Ко., Лтд. Diarylthiohydantoin compound crystal

Cited By (20)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2017071375A1 (en) * 2015-10-30 2017-05-04 成都海创药业有限公司 Crystal form of deuterated imidazolone compound, and preparation method and use therefor
TWI638810B (en) 2015-10-30 2018-10-21 成都海創藥業有限公司 Crystal form i of deuterium labelled imidazolone compounds and preparation and use thereof
CN106432090B (en) * 2015-10-30 2019-08-20 成都海创药业有限公司 A kind of crystal form and its preparation method and application of deuterated imidazoquinolone compounds
CN106432090A (en) * 2015-10-30 2017-02-22 成都海创药业有限公司 Crystal form of deuteration imidazolone compound and preparation method and use of crystal form
JP7241682B2 (en) 2016-10-17 2023-03-17 ヒノバ ファーマシューティカルズ インコーポレイテッド Method for preparing deuterated imidazolidinedione compounds
JP2019532075A (en) * 2016-10-17 2019-11-07 ヒノバ ファーマシューティカルズ インコーポレイテッド Process for preparing deuterated imidazolidinedione compounds
CN111032644A (en) * 2017-08-07 2020-04-17 正大天晴药业集团股份有限公司 Diarylthiohydantoin compounds useful as androgen receptor antagonists
US11866433B2 (en) 2017-08-07 2024-01-09 Chia Tai Tianqing Pharmaceutical Group Co., Ltd. Diarylthiohydantoin compound as androgen receptor antagonist
US11332465B2 (en) 2017-08-07 2022-05-17 Chia Tai Tianqing Pharmaceutical Group Co., Ltd. Diarylthiohydantoin compound as androgen receptor antagonist
CN111032644B (en) * 2017-08-07 2021-08-10 正大天晴药业集团股份有限公司 Diarylthiohydantoin compounds useful as androgen receptor antagonists
JP2021519322A (en) * 2018-03-29 2021-08-10 ヒノバ ファーマシューティカルズ インコーポレイテッド Deuterated imidazolidinedione compounds and their uses
JP2022065014A (en) * 2018-03-29 2022-04-26 ヒノバ ファーマシューティカルズ インコーポレイテッド Deuterated imidazolidinedione compounds and their uses
CN113439083A (en) * 2019-02-01 2021-09-24 正大天晴药业集团股份有限公司 Crystal of diarylthiohydantoin compound
JP2022518605A (en) * 2019-02-01 2022-03-15 正大天晴▲藥▼▲業▼集▲団▼股▲フン▼有限公司 Diarylthiohydantoin compound crystals
JP7464613B2 (en) 2019-02-01 2024-04-09 正大天晴▲藥▼▲業▼集▲団▼股▲フン▼有限公司 Diarylthiohydantoin compound crystals
CN113439083B (en) * 2019-02-01 2023-01-24 正大天晴药业集团股份有限公司 Crystal of diarylthiohydantoin compound
WO2020156448A1 (en) * 2019-02-01 2020-08-06 正大天晴药业集团股份有限公司 Crystal of diarylthiohydantoin compound
RU2810214C2 (en) * 2019-02-01 2023-12-25 Чиа Тай Тянцин Фармасьютикал Груп Ко., Лтд. Diarylthiohydantoin compound crystal
CN117164520A (en) * 2022-01-28 2023-12-05 南京思聚生物医药有限公司 Androgen receptor antagonist with local action and application thereof
CN115181043A (en) * 2022-07-27 2022-10-14 爱斯特（成都）生物制药股份有限公司 Method for preparing 4-isothiocyanato-2- (trifluoromethyl) benzonitrile by continuous flow

Similar Documents

Publication Publication Date Title
CN104341352A (en) Diaryl hydantoin compound as androgen receptor antagonist and applications of diaryl hydantoin compound
KR101536023B1 (en) Therapeutic uses of compounds having combined sert, 5-ht3 and 5-ht1a activity
CA2834778C (en) Method of treating cancer and bone cancer pain
KR101069612B1 (en) Halogenated selective androgen receptor modulators and methods of use thereof
CN102482317B (en) 17-hydroxy-17-pentafluorethyl-estra-4,9(10)-dien-11-aryl Derivatives, Methods For The Production Thereof And Use Thereof For Treating Diseases
CN109071426A (en) Substituted benzamide and its application method
CN102647985A (en) Methods of using c-Met modulators
CN105358522A (en) Ester derivatives of androgen receptor modulators and methods for their use
JP2006518328A (en) Heterocyclic selective androgen receptor modulator and method of using the same
US9994578B2 (en) Benzodiazepine derivative and use thereof
CN108727248A (en) A kind of diquaternary ammonium compound and its preparation method and application
CN106478502B (en) 1,2,3, 4-tetrahydroisoquinoline derivatives, preparation method and application thereof
CA2839301C (en) Nuclear receptor modulators and their use for the treatment and prevention of cancer
CN105646332A (en) Aminomethylpiperidine derivatives, and preparation method and pharmaceutical application thereof
CA2831932A1 (en) Combinations of akt and mek inhibitor compounds, and methods of use
Harikrishnan et al. Substituted benzyloxytricyclic compounds as retinoic acid-related orphan receptor gamma t (RORγt) agonists
CN104781241A (en) Crystalline compounds
TWI675820B (en) Novel compounds that specifically bind to AMPA receptors
CA2889381A1 (en) Carboxylic acid ester prodrug inhibitors of mek
CN103172577B (en) 4-amido quinazoline and 4-aminoquinoline compounds and uses thereof
CA3159749A1 (en) Salts and forms of an estrogen receptor modulator
WO2020063407A1 (en) N-aromatic amides compound and preparation method and use thereof
CN110023310A (en) For adjusting the biaryl composition and method of kinase cascade
BR122018007412B1 (en) PROCESS FOR PREPARATION OF ISOPROPYL ESTER OF (S)-(7-CYANO-4-PYRIDIN-2-ILMETHYL-1,2,3,4-TETRA-HYDROCYCLOPENTA[B]INDOL-2-YL)-CARBAMIC ACID, OR A PHARMACEUTICALLY ACCEPTABLE SALT OF THE SAME
WO2013143376A1 (en) Quinoline compounds containing 1,2,4-triazine-3,5-dione and use thereof

Legal Events

Date Code Title Description
C06 Publication
PB01 Publication
WD01 Invention patent application deemed withdrawn after publication
WD01 Invention patent application deemed withdrawn after publication

Application publication date: 20150211